ArticleProceedings of the National Academy of Sciences of the United States of America2016
Topological constraints and modular structure in the folding and functional motions of GlpG, an intramembrane protease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Resolving Conformational Heterogeneity in Intrinsically Disordered Proteins via Experimentally Guided Multi-Replica Simulations.bioRxiv : the preprint server for biology · 2026Article
- Steric trapping strategy for studying the folding of helical membrane proteins.Methods (San Diego, Calif.) · 2024Review
- Folding speeds of helical membrane proteins.Biochemical Society transactions · 2024Review
- Entangled Motifs in Membrane Protein Structures.International journal of molecular sciences · 2023Article
- How physical forces drive the process of helical membrane protein folding.EMBO reports · 2022Review
- Untangling the complexity of membrane protein folding.Current opinion in structural biology · 2022Review
- Cys-labeling kinetics of membrane protein GlpG: a role for specific SDS binding and micelle changes?Biophysical journal · 2021Article
- Phosphatidylglyerol Lipid Binding at the Active Site of an Intramembrane Protease.The Journal of membrane biology · 2020Review
- Structural cavities are critical to balancing stability and activity of a membrane-integral enzyme.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- On the Interpretation of Force-Induced Unfolding Studies of Membrane Proteins Using Fast Simulations.Biophysical journal · 2019Article
- Dynamic membrane topology in an unassembled membrane protein.Nature chemical biology · 2019Article
- Energy landscape underlying spontaneous insertion and folding of an alpha-helical transmembrane protein into a bilayer.Nature communications · 2018Article
- Modeling Membrane Protein-Ligand Binding Interactions: The Human Purinergic Platelet Receptor.The journal of physical chemistry. B · 2016Article
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5 authors.
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Abstract
We investigate the folding of GlpG, an intramembrane protease, using perfectly funneled structure-based models that implicitly account for the absence or presence of the membrane. These two models are used to describe, respectively, folding in detergent micelles and folding within a bilayer, which effectively constrains GlpG's topology in unfolded and partially folded states. Structural free-energy landscape analysis shows that although the presence of multiple folding pathways is an intrinsic property of GlpG's modular functional architecture, the large entropic cost of organizing helical bundles in the absence of the constraining bilayer leads to pathways that backtrack (i.e., local unfolding of previously folded substructures is required when moving from the unfolded to the folded state along the minimum free-energy pathway). This backtracking explains the experimental observation of thermodynamically destabilizing mutations that accelerate GlpG's folding in detergent micelles. In contrast, backtracking is absent from the model when folding is constrained within a bilayer, the environment in which GlpG has evolved to fold. We also characterize a near-native state with a highly mobile transmembrane helix 5 (TM5) that is significantly populated under folding conditions when GlpG is embedded in a bilayer. Unbinding of TM5 from the rest of the structure exposes GlpG's active site, consistent with studies of the catalytic mechanism of GlpG that suggest that TM5 serves as a substrate gate to the active site.
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